Abstract
Background
Gastrointestinal stromal tumors (GISTs) are believed to originate from the interstitial cells of Cajal (ICCs) or from the precursors of ICCs. Most GISTs show an activating mutation in either the c-kit or platelet-derived growth factor receptor α (PDGFRA) gene that results in a constitutive, ligand-independent activation of receptor tyrosine kinases. These gene mutations may play an important role in transforming a GIST progenitor cell into a tumor cell during the early phase of GIST tumorigenesis. However, the precise mechanism of the tumorigenesis is not known.
Methods
We examined ten patients with sporadic GIST for mutations in the tumor and its adjacent ICC cells, and compared the mutational status of ICC cells with that of the GIST cells in each patient. All cases were screened for mutations in the c-kit gene (exons 9, 11, 13, and 17) and in the PDGFRA gene (exons 12 and 18). Samples were limited to GIST cases from the small intestine, where ICCs were present in bundles and were considered suitable for isolation by laser capture microdissection.
Results
Of the ten tumors screened, eight had mutations in the c-kit gene (all in exon 11) and two were wild-type, whereas none of the ICCs exhibited mutations in these genes.
Conclusions
Our results suggest that ICCs adjacent to overt GISTs did not have mutations in the c-kit or PDGFRA genes, and overt GISTs may develop after the local and sporadic acquisition of these gene mutations, together with additional events.
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References
Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–80.
Miettinen M, Virolainen M, Maarit SR. Gastrointestinal stromal tumors-value of CD34 antigen in their identification and separation from true leiomyomas and schwannomas. Am J Surg Pathol. 1995;19:207–16.
Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol. 1998;152:1259–69.
Nishida T, Hirota S, Taniguchi M, Hashimoto K, Isozaki K, Nakamura H, et al. Familial gastrointestinal stromal tumors with germline mutation of the KIT gene. Nature Genet. 1998;19:323–4.
Kim HJ, Lim SJ, Park K, Yuh YJ, Jang SJ, Choi J. Multiple gastrointestinal stromal tumors with a germline c-kit mutation. Pathol Int. 2005;55:655–9.
Hartmann K, Wardelmann E, Ma Y, Merkelbach-Bruse S, Preussner LM, Woolery C, et al. Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis. Gastroenterology. 2005;129:1042–6.
Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708–10.
Heinrich MC. Molecular basis for treatment of gastrointestinal stromal tumors. Eur J Cancer Suppl. 2006;4:10–8.
Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001;344:1052–6.
Debiec-Rychter M, Sciot R, Le Cesne A, Schlemmer M, Hohenberqer P, van Oosterom AT, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors. Eur J Cancer. 2006;42:1093–103.
Tuveson DA, Willis NA, Jacks T, Griffin JD, Singer S, Fletcher CD, et al. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene. 2001;20:5054–8.
Corless CL, McGreevey L, Haley A, Town A, Heinrich MC. KIT mutations are common in incidental gastrointestinal stromal tumors 1 cm or less in size. Am J Pathol. 2002;160:1567–72.
Chen H, Hirota S, Isozaki K, Sun H, Ohashi A, Kinoshita K. Polyclonal nature of diffuse proliferation of interstitial cells of Cajal in patients with familial and multiple gastrointestinal stromal tumors. Gut. 2002;51:793–6.
Gjerdrum LM, Hamilton-Dutoit S. Laser-assisted microdissection of membrane-mounted tissue sections. Meth Mol Biol. 2005;293:127–38.
Kumada T, Tsuneyama K, Hatta H, Ishizawa S, Takano Y. Improved 1-h rapid immunostaining method using intermittent microwave irradiation: practicability based on 5 years application in Toyama Medical and Pharmaceutical University Hospital. Mod Pathol. 2004;17:1141–9.
Gjerdrum LM, Hamilton-Dutoit S. Laser-assisted microdissection of membrane-mounted sections following immunohistochemistry and in situ hybridization. Meth Mol Biol. 2005;293:139–49.
Bucher P, Villiger P, Egger JF, Buhler LH, Morel P. Management of gastrointestinal stromal tumors: from diagnosis to treatment. Swiss Med Wkly. 2004;134:145–53.
Espinosa I, Lee CH, Kim MK, Rouse BT, Subramanian S, Montqomery K, et al. A novel monoclonal antibody against DOG1 is a sensitive and specific marker for gastrointestinal stromal tumors. Am J Surg Pathol. 2008;32:210–8.
Torihashi S, Horisawa M, Watanabe Y. c-kit immunoreactive interstitial cells in the human gastrointestinal tract. J Auton Nerv Syst. 1999;75:38–50.
Miettinen M, El-Rifai W, Sobin L, Lasota J. Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. Hum Pathol. 2002;33:478–83.
Sommer G, Agosti V, Ehlers I, Rossi F, Corbacioglu S, Farkas J, et al. Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc Natl Acad Sci USA. 2003;100:6706–11.
Rubin BP, Antonescu CR, Scott-Browne JP, Comstock ML, Gu Y, Tanas MR, et al. A knock-in mouse model of gastrointestinal stromal tumor harboring KIT K641E. Cancer Res. 2005;65:6631–9.
Nakai N, Ishikawa T, Nishitani A, Liu NN, Shincho M, Hao H, et al. A mouse model of a human multiple GIST family with KIT-Asp820Tyr mutation generated by a knock-in strategy. J Pathol. 2008;214:302–11.
Kawanowa K, Sakuma Y, Sakurai S, Hishima T, Iwasaki Y, Saito K, et al. High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum Pathol. 2006;37:1527–35.
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Nakajima, T., Miwa, S., Ando, T. et al. Interstitial cells of Cajal do not harbor c-kit or PDGFRA gene mutations in patients with sporadic gastrointestinal stromal tumors. J Gastroenterol 44, 426–431 (2009). https://doi.org/10.1007/s00535-009-0032-z
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DOI: https://doi.org/10.1007/s00535-009-0032-z